MitoQ Triggers Mitochondrial Collapse and Apoptotic Death in Glioblastoma Associated with KATP Channel Expression...

Glioblastoma (GBM) is the most aggressive primary brain tumor and remains refractory to current therapies due to its pronounced metabolic heterogeneity and mitochondrial adaptability. Ion channels, particularly ATP-sensitive-potassium (KATP) channels, have emerged as critical regulators of cellular energy sensing in cancer. This study evaluated the mitochondrial-targeted agent MitoQ in GBM and explored its potential association with KATP channels. In this study, the cytotoxic potential of MitoQ was systematically evaluated in three genetically distinct GBM cell lines. Cell viability was assessed using concentration-response analyses to identify differential sensitivity. Baseline expression of KATP-channel components (KCNJ11/Kir6.2, ABCC8/SUR1, and CCDC51) was quantified by qRT-PCR and Western blotting. Mechanistic analyses were subsequently performed in the most sensitive cell line and included mitochondrial ROS measurement (MitoSOX), confocal assessment of mitochondrial morphology, Seahorse XF-based bioenergetic profiling, ATP/ADP ratio quantification, analysis of autophagic flux via LC3-II/p62 turnover with bafilomycin-A1, and caspase-3/7-based apoptosis detection. U87 cells exhibited the lowest IC₅₀ for MitoQ and showed significantly higher baseline expression of KATP channel subunits compared to U251 and T98G cells. Acute MitoQ exposure (10 µM, 6 h) in U87 cells induced marked mitochondrial superoxide accumulation, extensive mitochondrial fragmentation, severe suppression of oxidative phosphorylation, and ATP depletion. These effects were associated with selective downregulation of Kir6.2 and the mitochondrial KATP-associated component CCDC51, impaired autophagic flux with p62 accumulation, and robust activation of executioner caspases. In conclusion, MitoQ may induce mitochondrial dysfunction in metabolically primed GBM cells, and cellular sensitivity appears to correlate with a distinct KATP channel expression signature.